he allele-specific peptidebinding motifs of major histocompatibility complex (MHC) proteins, originally discovered by pool sequencing of MHC class I-bound peptides 1 , provide a biochemical basis for the phenomenon of MHC restriction of T-cell responses. However, the analysis of class II peptide motifs has proved difficult due to the heterogeneity in peptide length [2][3][4] . This problem has been overcome using several approaches to characterize the binding motifs of human HLA-DR class II proteins (reviewed in Ref. 5). The understanding of the specificity of peptide-MHC class II interactions was greatly facilitated by the three-dimensional structures of HLA-DR1 (Ref. 6) and of its complex with a peptide 7 . Similar to class I molecules, the HLA-DR structure revealed pockets in the peptide-binding groove accommodating several 'anchor' residues in a peptide. The specificity of these pockets is influenced by polymorphic residues, resulting in allele-specific class II motifs.
The consensus core sequence of peptides binding to HLA-DR appears to be a nonamer with anchor residues at positions 1, 4, 6 and 9 (Ref. 5). Position 1 (P1) appears critical for binding and is invariably occupied by either aromatic or aliphatic residues. In addition, the murine class II I-E molecules, which are closely homologous to HLA-DR, were shown to be similar in their structure 8 and binding motifs 9,10 . The amino acid usage at the anchor positions in DR/I-E motifs seems to be more flexible than in class I motifs, allowing several possible residues at each position. Nevertheless, the overall combination of several positions results in a stringent binding motif.
In contrast to the well-characterized DR/I-E motifs, the peptidebinding specificity of human HLA-DQ and particularly of the murine H-2A (I-A) MHC class II proteins is controversial.
Binding motifs of I-A molecules: recent progress
To uncover the general rules for I-A binding specificity, peptide binding to several murine I-A molecules has been studied [16][17][18][19][20][21][22] . Importantly, these studies suggest a strong similarity in the organization of